tbuckley/cabot-search huggingface dataset:
Contribution of Type H Blood Vessels to Pathologic Osteogenesis and Inflammation in an Experimental Spondyloarthritis Model
Authors: Merlijn H. Kaaij, Jan Piet van Hamburg, Charlotte C. N. van Rooijen, Anika Grüneboom, Yik Y. Kan, Desiree Pots, Georg Schett, Leo J. van Ruijven, Leonie M. van Duivenvoorde, Leonie F. A. Huitema, Dominique L. P. Baeten, Sander W. Tas
Journal: Arthritis & Rheumatology (2023)

Spondyloarthritis (SpA) is characterized by pathologic osteogenesis, inflammation, and extensive angiogenesis in axial and peripheral tissues. Current therapies effectively target inflammation, but these therapies lack efficacy in preventing pathologic osteogenesis. Transgenic mice overexpressing transmembrane tumor necrosis factor (tmTNF-Tg mice) exhibit SpA-like features. We hypothesized that type H blood vessels, which are implicated in osteogenesis, are increased and contribute to pathology in this experimental SpA model.We analyzed ankles, femora, and vertebrae of tmTNF-Tg mice and nontransgenic littermates and tmTNF-Tg mice on either a TNF receptor type I (TNFRI)-deficient or TNF receptor type II (TNFRII)-deficient background for osteogenesis, angiogenesis, and inflammation using advanced imaging technologies at various stages of disease.Compared to nontransgenic littermates, tmTNF-Tg mice exhibited an increase in vertebral type H vessels and osteoprogenitor cells in subchondral bone. These features of increased angiogenesis and osteogenesis were already present before onset of clinical disease symptoms. Type H vessels and osteoprogenitor cells were in close proximity to inflammatory lesions and ectopic lymphoid structures. The tmTNF-Tg mice also showed perivertebral ectopic type H vessels and osteogenesis, an increased number of vertebral transcortical vessels, and enhanced entheseal angiogenesis. In tmTNF-Tg mice crossed on a TNFRI- or TNFRII-deficient background, no clear reduction in type H vessels was shown, suggesting that type H vessel formation is not exclusively mediated via TNFRI or TNFRII.The contribution of type H vessels to pathologic osteogenesis in experimental SpA advances our knowledge of the pathophysiology of this disease and may also provide a novel opportunity for targeted intervention.
Epigenetic–Metabolic Interplay in the DNA Damage Response and Therapeutic Resistance of Breast Cancer
Authors: Chandrima Das, Swagata Adhikari, Apoorva Bhattacharya, Sanjukta Chakraborty, Payel Mondal, Shalini S. Yadav, Santanu Adhikary, Clayton R. Hunt, Kamlesh K. Yadav, Shruti Pandita, Siddhartha Roy, John A. Tainer, Zamal Ahmed, Tej K. Pandita
Journal: Cancer Research (2023)

Abstract Therapy resistance is imposing a daunting challenge on effective clinical management of breast cancer. Although the development of resistance to drugs is multifaceted, reprogramming of energy metabolism pathways is emerging as a central but heterogenous regulator of this therapeutic challenge. Metabolic heterogeneity in cancer cells is intricately associated with alterations of different signaling networks and activation of DNA damage response pathways. Here we consider how the dynamic metabolic milieu of cancer cells regulates their DNA damage repair ability to ultimately contribute to development of therapy resistance. Diverse epigenetic regulators are crucial in remodeling the metabolic landscape of cancer. This epigenetic–metabolic interplay profoundly affects genomic stability of the cancer cells as well as their resistance to genotoxic therapies. These observations identify defining mechanisms of cancer epigenetics–metabolism–DNA repair axis that can be critical for devising novel, targeted therapeutic approaches that could sensitize cancer cells to conventional treatment strategies.
Characterization of Applicant Preference Signals, Invitations for Interviews, and Inclusion on Match Lists for Residency Positions in Urology
Authors: Ralph Grauer, Daniel Ranti, Kirsten Greene, Michael A. Gorin, Mani Menon, Saša Zorc
Journal: JAMA Network Open (2023)

Importance Preference signals were to be implemented in over 15 specialties during the 2022-2023 residency match. Analyzing results from the implementation of signals during the American Urological Association (AUA) urology match may inform future behavior. Objective To characterize applicant and program signal usage and results in the Society of Academic Urology and AUA databases with respect to interview invites and rank list creation. Design, Setting, and Participants This cohort study involved all applicants and residencies in the 2021-2022 AUA match with data analysis conducted in April through July 2022. Exposures Five signals indicating interest. Main Outcomes and Measures Using verified match and survey data reported by applicants and programs, a logistic regression was performed on applicant factors associated with obtaining an interview—the main outcome (using inclusion on rank list as a proxy): age, gender, degree (MD or DO), dispersal of signal, US senior status, racial minority group status, Latino ethnicity, international medical graduate status, presence of a home program, AUA geographic section, and US Medical Licensing Examination Step 1 score. Applicant signal dispersal strategies were stratified by applicant and program competitiveness, as well as program behavior upon receipt of signal with respect to extending interviews and rank list ordering of applicants. Results A total of 2659 signals were sent by 553 candidates (mean [SD] age, 27.4 [2.9] years; 179 female [32.4%], 154 racial minority candidates [38.8%]) submitting rank lists for 364 positions at 143 programs. Programs received a median (IQR) of 352 (295-411) applications and were signaled to a median of 16 (8-26) times each. In a logistic regression estimating interview status, geographic proximity (OR, 3.25; 95% CI, 2.05-5.15; P = .001) and signal status (OR, 6.04; 95% CI, 3.50-10.40; P &amp;amp;lt; .001) were associated with receiving an interview. Using multiple imputation by chained equations to impute missing data and broadening the data set, male gender (OR, 0.64; 95% CI, 0.45-0.92; P = .04) and international medical graduate status (OR, 0.35; 95% CI, 0.15-0.81; P = .04) were negative variables, while MD degree (OR, 2.36; 95% CI, 1.27-4.36; P = .02) and US senior status (OR, 1.91; 95% CI, 1.13-3.23; P = .04) were positive variables. Conclusions and Relevance This study of the usage and trends of the newly added preference signals reported the most common strategies for signal dispersal; in an analysis of factors involved in obtaining an interview, geographic similarity between applicant and program and preference signal usage were associated with successful applications.
Using artificial neural networks to ask ‘why’ questions of minds and brains
Authors: Nancy Kanwisher, Meenakshi Khosla, Katharina Dobs
Journal: Trends in Neurosciences (2023)

Neuroscientists have long characterized the properties and functions of the nervous system, and are increasingly succeeding in answering how brains perform the tasks they do. But the question 'why' brains work the way they do is asked less often. The new ability to optimize artificial neural networks (ANNs) for performance on human-like tasks now enables us to approach these 'why' questions by asking when the properties of networks optimized for a given task mirror the behavioral and neural characteristics of humans performing the same task. Here we highlight the recent success of this strategy in explaining why the visual and auditory systems work the way they do, at both behavioral and neural levels.
Venous thromboembolism after <scp>COVID</scp>‐19 vaccination in patients with thrombophilia
Authors: Damon E. Houghton, Waldemar E. Wysokinski, Leslie J. Padrnos, Surbhi Shah, Ewa Wysokinska, Rajiv Pruthi, Atefeh Ghorbanzadeh, Aneel Ashrani, Meera Sridharan, Robert D. McBane, Anand Padmanabhan, Ana I. Casanegra
Journal: American Journal of Hematology (2023)

Abstract Patients with thrombophilia remain concerned about venous thromboembolism (VTE) risk with COVID‐19 vaccinations. The aim of this study was to examine VTE outcomes in patients with inherited or acquired thrombophilia who were vaccinated for COVID‐19. Vaccinated patients ≥18 years between November 1, 2020 and November 1, 2021 were analyzed using electronic medical records across the Mayo Clinic enterprise. The primary outcome was imaging confirmed acute VTE occurring 90 days before and after the date of the first vaccine dose. Thrombophilia patients were identified through laboratory testing results and ICD‐10 codes. A total of 792 010 patients with at least one COVID‐19 vaccination were identified. Six thousand sixty‐seven of these patients were found to have a thrombophilia, among whom there was a total of 39 VTE events after compared to 51 VTE events before vaccination (0.64% vs. 0.84%, p = .20). In patients with Factor V Leiden or prothrombin gene mutation, VTE occurred in 27 patients before and in 29 patients after vaccination (0.61 vs. 0.65%, p = .79). In patients with antiphospholipid syndrome, VTE occurred in six patients before and four patients after vaccination (0.59% vs. 0.39%, p = .40). No difference was observed in the overall VTE rate when comparing the postvaccination 90 days to the prevaccination 90 days, adjusted hazard ratio 0.81 (95% confidence interval: 0.53–1.23). In this subgroup of COVID‐19 vaccinated patients with thrombophilia, there was no increased risk for acute VTE postvaccination compared to the prevaccination timeframe. These results are consistent with prior studies and should offer additional reassurance to patients with inherited or acquired thrombophilia.
The Circadian Biology of Heart Failure
Authors: Nadim El Jamal, Ronan Lordan, Sarah L. Teegarden, Tilo Grosser, Garret FitzGerald
Journal: Circulation Research (2023)

Driven by autonomous molecular clocks that are synchronized by a master pacemaker in the suprachiasmatic nucleus, cardiac physiology fluctuates in diurnal rhythms that can be partly or entirely circadian. Cardiac contractility, metabolism, and electrophysiology, all have diurnal rhythms, as does the neurohumoral control of cardiac and kidney function. In this review, we discuss the evidence that circadian biology regulates cardiac function, how molecular clocks may relate to the pathogenesis of heart failure, and how chronotherapeutics might be applied in heart failure. Disrupting molecular clocks can lead to heart failure in animal models, and the myocardial response to injury seems to be conditioned by the time of day. Human studies are consistent with these findings, and they implicate the clock and circadian rhythms in the pathogenesis of heart failure. Certain circadian rhythms are maintained in patients with heart failure, a factor that can guide optimal timing of therapy. Pharmacologic and nonpharmacologic manipulation of circadian rhythms and molecular clocks show promise in the prevention and treatment of heart failure.
Successful dose reduction of dupilumab in atopic dermatitis
Authors: Michael R Ardern-Jones, Emily E Buchanan, Samba Njungu, Daniel O’Driscoll
Journal: British Journal of Dermatology (2023)

Current UK, European and USA atopic dermatitis guidelines do not currently advise on the possibility of dose reduction of dupilumab therapy below the licensed dose of 300 mg subcutaneously every 2 weeks for adults. Here, we report preliminary findings to suggest that in those who respond well to the licensed dose, dupilumab dosing can be reduced while maintaining good disease control. We propose a randomized controlled clinical trial to further analyse the cost effectiveness of this approach.
Mitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable?
Authors: Shanelle R. Shillingford, Anton M. Bennett
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Phosphatases and kinases maintain an equilibrium of dephosphorylated and phosphorylated proteins, respectively, that are required for critical cellular functions. Imbalance in this equilibrium or irregularity in their function causes unfavorable cellular effects that have been implicated in the development of numerous diseases. Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of protein substrates on tyrosine residues, and their involvement in cell signaling and diseases such as cancer and inflammatory and metabolic diseases has made them attractive therapeutic targets. However, PTPs have proved challenging in therapeutics development, garnering them the unfavorable reputation of being undruggable. Nonetheless, great strides have been made toward the inhibition of PTPs over the past decade. Here, we discuss the advancement in small-molecule inhibition for the PTP subfamily known as the mitogen-activated protein kinase (MAPK) phosphatases (MKPs). We review strategies and inhibitor discovery tools that have proven successful for small-molecule inhibition of the MKPs and discuss what the future of MKP inhibition potentially might yield.
Targeting ferroptosis in cardio‐metabolic‐diseases: Mechanisms and therapeutic prospects
Authors: Jia‐Bao Zhang, Jie Tong, Di‐Yang Sun, Jiang‐Tao Fu, Dong‐Jie Li, Pei Wang
Journal: Medicinal Research Reviews (2023)

Cardio-metabolic-diseases (cardio-metabolic-diseases) are leading causes of death and disability worldwide and impose a tremendous burden on whole society as well as individuals. As a new type of regulated cell death (RCD), ferroptosis is distinct from several classical types of RCDs such as apoptosis and necroptosis in cell morphology, biochemistry, and genetics. The main molecular mechanisms of ferroptosis involve iron metabolism dysregulation, mitochondrial malfunction, impaired antioxidant capacity, accumulation of lipid-related peroxides and membrane disruption. Within the past few years, mounting evidence has shown that ferroptosis contributes to the pathophysiological process in cardio-metabolic-diseases. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This review comprehensively summarizes the mechanism of ferroptosis in the development and progression of cardio-metabolic-diseases, so as to provide new insights for cardio-metabolic-diseases pathophysiology. Moreover, we highlight potential druggable molecules in ferroptosis signaling pathway, and discuss recent advances in management strategies by targeting ferroptosis for prevention and treatment of cardio-metabolic-diseases.
Fibrin clot properties in cardiovascular disease: from basic mechanisms to clinical practice
Authors: Michał Ząbczyk, Robert A S Ariëns, Anetta Undas
Journal: Cardiovascular Research (2023)

Fibrinogen conversion into insoluble fibrin and the formation of a stable clot is the final step of the coagulation cascade. Fibrin clot porosity and its susceptibility to plasmin-mediated lysis are the key fibrin measures, describing the properties of clots prepared ex vivo from citrated plasma. Cardiovascular disease (CVD), referring to coronary heart disease, heart failure, stroke, and hypertension, has been shown to be associated with the formation of dense fibrin networks that are relatively resistant to lysis. Denser fibrin mesh characterized acute patients at the onset of myocardial infarction or ischaemic stroke, while hypofibrinolysis has been identified as a persistent fibrin feature in patients following thrombotic events or in those with stable coronary artery disease. Traditional cardiovascular risk factors, such as smoking, diabetes mellitus, hyperlipidaemia, obesity, and hypertension, have also been linked with unfavourably altered fibrin clot properties, while some lifestyle modifications and pharmacological treatment, in particular statins and anticoagulants, may improve fibrin structure and function. Prospective studies have suggested that prothrombotic fibrin clot phenotype can predict cardiovascular events in short- and long-term follow-ups. Mutations and splice variants of the fibrinogen molecule that have been proved to be associated with thrombophilia or increased cardiovascular risk, along with fibrinogen post-translational modifications, prothrombotic state, inflammation, platelet activation, and neutrophil extracellular traps formation, contribute also to prothrombotic fibrin clot phenotype. Moreover, about 500 clot-bound proteins have been identified within plasma fibrin clots, including fibronectin, α2-antiplasmin, factor XIII, complement component C3, and histidine-rich glycoprotein. This review summarizes the current knowledge on the mechanisms underlying unfavourable fibrin clot properties and their implications in CVD and its thrombo-embolic manifestations.
Gut check: assessing the role of the gut microbiota in the adverse cardiovascular effects of obstructive sleep apnoea
Authors: David J. Durgan, Ramon Farré
Journal: European Respiratory Journal (2023)

<b>Obstructive sleep apnoea (OSA) disrupts the gut microbiota, contributing to adverse cardiovascular effects. Clinical research on patients9 gut microbiota may help in finding treatments preventing OSA-associated cardiovascular outcomes.</b>https://bit.ly/3TygLl4
Venous thromboembolism incidence and risk factors associated with immune checkpoint inhibitors among patients with advanced non-small cell lung cancer
Authors: Alok A Khorana, Jennell Palaia, Lisa Rosenblatt, Radhika Pisupati, Ning Huang, Chi Nguyen, John Barron, Kerrin Gallagher, T Christopher Bond
Journal: Journal for ImmunoTherapy of Cancer (2023)

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in patients with lung cancer. Systemic therapies, such as chemotherapy (chemo), are associated with increased risk of VTE. Immune checkpoint inhibitors (ICIs) are a new standard of care for the treatment of lung cancer, but their association with VTE is not fully understood. We evaluated the incidence of VTE and risk factors for patients with advanced non-small cell lung cancer (aNSCLC) treated with first-line ICI-based, chemo-based, or ICI+chemo regimens.This retrospective cohort study used HealthCore Integrated Research Environment - Oncology data, an integrated database of administrative claims, coupled with clinical data from a cancer-care quality program. Patients with first-line treatment of stage IV non-small cell lung cancer from July 2014 to August 2020 were grouped based on three treatment types: ICI-based, chemo-based, or ICI+chemo. Patients with VTE before initiation of systemic treatment were excluded. Newly diagnosed VTE events were identified via inpatient and outpatient diagnosis codes. Cox proportional hazards models were used to investigate the factors associated with VTE risk.Among 2299 eligible patients (ICI-based, n=605; chemo-based, n=1092; ICI+chemo, n=602) with a median follow-up of 9.1 months, the VTE incidence rates (95% CI) per 100 person-years were 17.8 (95% CI 16.0 to 19.5) overall, 13.5 (95% CI 10.6 to 16.5) for ICI-based, 18.0 (95% CI 15.5 to 20.5) for chemo-based, and 22.4 (95% CI 20.2 to 24.5) for ICI+chemo. The 6-month cumulative incidence of VTE was 8.1% for ICI-based, 10.9% for chemo-based, and 12.8% for ICI+chemo. Pulmonary embolism was most common, accounting for 63% of the VTE events. After controlling for baseline patient characteristics, the risk of VTE was 26% lower for ICI-based regimens than for chemo-based regimens (HR 0.74, p=0.03). There was no meaningful difference in the risk between ICI+chemo and chemo-based regimens (HR 1.12, p=0.36). Previous radiation and severe obesity (body mass index ≥40) were associated with VTE.VTE incidence rate per 100 person-years was common across regimens in patients with aNSCLC, but numerically lower for patients receiving ICI-based regimens compared with those receiving chemo-based and ICI+chemo regimens. VTE is a common complication of lung cancer, and there is a continued need for awareness of VTE as a comorbidity in this population.
Lipoxin Mimetics and the Resolution of Inflammation
Authors: Catherine Godson, Patrick Guiry, Eoin Brennan
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Inflammation and its timely resolution are critical to ensure effective host defense and appropriate tissue repair after injury and or infection. Chronic, unresolved inflammation typifies many prevalent pathologies. The key mediators that initiate and drive the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. More recently, there is a growing appreciation that specific mediators, including arachidonate-derived lipoxins, are generated in self-limiting inflammatory responses to promote the resolution of inflammation and endogenous repair mechanisms without compromising host defense. We discuss the proresolving biological actions of lipoxins and recent efforts to harness their therapeutic potential through the development of novel, potent lipoxin mimetics generated via efficient, modular stereoselective synthetic pathways. We consider the evidence that lipoxin mimetics may have applications in limiting inflammation and reversing fibrosis and the underlying mechanisms.
A <scp>Genome‐Wide</scp> Association Study <scp>Meta‐Analysis</scp> of Alpha Angle Suggests <scp>Cam‐Type</scp> Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults
Authors: Benjamin G. Faber, Monika Frysz, April E. Hartley, Raja Ebsim, Cindy G. Boer, Fiona R. Saunders, Jennifer S. Gregory, Richard M. Aspden, Nicholas C. Harvey, Lorraine Southam, William Giles, Christine L. Le Maitre, J. Mark Wilkinson, Joyce B. J. van Meurs, Eleftheria Zeggini, Timothy Cootes, Claudia Lindner, John P. Kemp, George Davey Smith, Jonathan H. Tobias
Journal: Arthritis & Rheumatology (2023)

Objective To examine the genetic architecture of cam morphology using alpha angle (AA) as a proxy measure and conduct an AA genome‐wide association study (GWAS) followed by Mendelian randomization (MR) to evaluate its causal relationship with hip osteoarthritis (OA). Methods Observational analyses examined associations between AA measurements derived from hip dual x‐ray absorptiometry (DXA) scans from the UK Biobank study and radiographic hip OA outcomes and subsequent total hip replacement. Following these analyses, an AA GWAS meta‐analysis was performed (N = 44,214) using AA measurements previously derived in the Rotterdam Study. Linkage disequilibrium score regression assessed the genetic correlation between AA and hip OA. Genetic associations considered significant ( P &lt; 5 × 10 −8 ) were used as AA genetic instrument for 2‐sample MR analysis. Results DXA‐derived AA showed expected associations between AA and radiographic hip OA (adjusted odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.58, 1.67]) and between AA and total hip replacement (adjusted hazard ratio 1.45 [95% CI 1.33, 1.59]) in the UK Biobank study cohort. The heritability of AA was 10%, and AA had a moderate genetic correlation with hip OA (r g = 0.26 [95% CI 0.10, 0.43]). Eight independent genetic signals were associated with AA. Two‐sample MR provided weak evidence of causal effects of AA on hip OA risk (inverse variance weighted OR 1.84 [95% CI 1.14, 2.96], P = 0.01). In contrast, genetic predisposition for hip OA had stronger evidence of a causal effect on increased AA (inverse variance weighted β = 0.09 [95% CI 0.04, 0.13], P = 4.58 × 10 −5 ). Conclusion Expected observational associations between AA and related clinical outcomes provided face validity for the DXA‐derived AA measurements. Evidence of bidirectional associations between AA and hip OA, particularly for risk of hip OA on AA, suggests that hip shape modeling secondary to a genetic predisposition to hip OA contributes to the well‐established relationship between hip OA and cam morphology in older adults.